Mechanisms of cerebral infarcts and brain oxygen utilization in anemia

项目摘要 而脑氧输送取决于脑血流量（CBF; ml血液/100 g组织/分钟）， 随着血液氧含量的增加，人们越来越认识到，毛细血管通过时间本身也可以 影响组织氧提取，即使在存在正常或升高的CBF的情况下。个体中 贫血，其中由于充血而可能存在加速的毛细血管流速， 脑自动调节，减少毛细血管通过时间可导致组织氧时间减少 卸载。令人信服的证据已经提供了不均匀的毛细管流动的基础异常 在多种情况下的氧输送，包括急性缺血性中风中的梗塞扩大、创伤性脑 损伤和阿尔茨海默病。在镰状细胞性贫血（SCA）中，我们观察到快速毛细血管通过， 在动脉自旋标记（ASL）CBF加权MRI上可见，存在于超过50%的成人和儿童中。 我们在已发表的工作和来自154名SCA成人和儿童的初步数据中表明， 硬脑膜静脉窦内的高信号ASL信号与动脉抬高直接相关， 速度、升高的CBF和降低的氧提取分数（OEF;消耗的氧与氧的比率 输送），并且这种效应可能会减少以下输血治疗，这些输血治疗可改善氧气输送， 组织.这些发现表明，ASL图像上的静脉高信号可能是 氧交换效率的毛细管水平干扰。我们最有影响力的发现之一是， 初步的工作是，我们已经观察到，快速毛细血管水平的动静脉通过与 氧代谢减少，这表明这些转运时间可能提供了一个生物标志物， 脑梗死风险大于50%的SCA患者的脑缺血 30岁，但往往缺乏传统的中风危险因素。在这里，我们建议改进神经成像， 用于评估动静脉通过以允许毛细血管通过时间的可靠定量测量的方法 非侵入性地在体内，并随后测试有关脑氧利用的基本假设 在有与无梗死的贫血个体中。目的（1）：应用创新的ASL MRI方法和时间 对健康对照组和SCA参与者的主要颅内动脉和硬脑膜窦进行回归分析。 目的（2）：量化SCA参与者在血液治疗前后的脑毛细血管通过时间 输血以了解血红蛋白的增加如何与脑氧摄取的改善并行。 目的（3）：检验以下假设：SCA患者的动静脉通过时间缩短， 与无梗死组相比。短期目标是利用非侵入性成像方法来了解 贫血中氧利用和神经血管功能障碍的机制。长期目标是 利用这些信息对贫血患者进行分类，以进行个性化的中风预防治疗， 并客观地量化这些疗法对大脑健康的影响。

PROJECT SUMMARY While cerebral oxygen delivery depends on the cerebral blood flow (CBF; ml blood/100g tissue/minute) and blood oxygen content, it is becoming increasingly recognized that blood capillary transit time itself can also influence tissue oxygen extraction, even in the presence of normal or elevated CBF. In individuals with anemia where accelerated capillary flow velocities may be present as a result of hyperemia and cerebral autoregulation, reduced capillary transit time can lead to reduced times for tissue oxygen offloading. Compelling evidence has been provided for heterogeneous capillary flow underlying abnormal oxygen delivery in multiple conditions including expansion of infarcts in acute ischemic stroke, traumatic brain injury, and Alzheimer's disease. In sickle cell anemia (SCA), we have observed that rapid capillary transit, visible on arterial spin labeling (ASL) CBF-weighted MRI, is present in more than 50% of adults and children. We have shown in published work and preliminary data from 154 adults and children with SCA that hyperintense ASL signal within cerebral dural venous sinuses is directly associated with elevated arterial velocities, elevated CBF, and reduced oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), and that this effect may reduce following transfusion therapies that improve oxygen delivery to tissue. These findings indicate that venous hyperintense signal on ASL images may represent a marker of capillary-level disturbances in oxygen exchange efficiency. One of the most impactful findings of our preliminary work is that we have observed that rapid capillary-level arterio-venous transit is associated with reduced oxygen metabolism, suggesting that these transit times may provide a biomarker of cerebral ischemia in individuals with SCA who have greater than a 50% risk of cerebral infarcts by age 30 years, yet often lack conventional stroke risk factors. Here, we propose to refine neuroimaging methods for evaluating arterio-venous transit to allow for robust, quantitative measures of capillary transit time non-invasively in vivo, and subsequently to test fundamental hypotheses regarding cerebral oxygen utilization in anemic individuals with vs. without infarcts. Aim (1): To apply innovative ASL MRI methods and time regression analyses over major intracranial arteries and dural sinuses in healthy control and SCA participants. Aim (2): To quantify cerebral capillary transit time in SCA participants before and after treatment with blood transfusion to understand how increases in hemoglobin parallel an improvement in brain oxygen extraction. Aim (3): To test the hypothesis that arterio-venous transit times are reduced in individuals with SCA with versus without infarcts. The short-term goal is to utilize non-invasive imaging approaches to understand mechanisms of oxygen utilization and neurovascular dysfunction in anemia. The long-term goal is to use this information to triage individuals with anemia for personalized stroke prevention therapies, as well as to objectively quantify the impact of these therapies on brain health.